This invention relates to the isolation of high purity, natural d-alpha-tocopherol which is produced abundantly in nature, and which is the E vitamin of greatest activity. It also relates to the enhancement of the Vitamin E activity of a concentrate of mixed tocopherol homologues including beta-, delta- and gamma-tocopherols and which could include tocotrienols, which can be derived from natural plant sources. The instant invention achieves the separation of the beta-, delta- and gamma- homologues in high purity from the alpha-tocopherol; recovering the alpha-tocopherol and methylating the beta-, gamma- and delta- homologues to provide additional high purity alpha-tocopherol.
The term Vitamin E was originally used to designate the active component of certain vegetable oils. Vitamin E activity means the physiological activity of a group of nutrient materials originally isolated from various natural sources. The materials having Vitamin E activity all belong to a distinct series of compounds which are all derivatives of chroman-6-ol. These compounds are all tocol derivatives having an isoprenoid C.sub.16 -side chain. The term "tocol" is used to mean 2-methyl-2-(4', 8',12'-trimethyltridecyl) chroman-6-ol. The compounds of primary importance for Vitamin E activity are the methylated tocols, especially 5,7,8-trimethyl tocol. The nomenclature currently used for this compound is alpha-tocopherol; 5,8-dimethyl tocol is betatocopherol, 7,8-dimethyl tocol is gamma-tocopherol, and 8-methyl tocol is delta-tocopherol. The tocopherol nomenclature will be used throughout.
The physiological activity of this group of compounds is measured by the ability to maintain fertility in rats. The Vitamin E active compounds have a variety of beneficial effects in humans with the alpha-tocopherol homologue having the highest potency as measured by its effectiveness in maintaining rat fertility. For this reason the term Vitamin E is frequently used interchangeably with d-alpha-tocopherol, the naturally occurring tocopherol of highest Vitamin E activity.
Alpha-tocopherol can also be prepared synthetically, although in commercial synthetic preparations the product is always present in admixture with its 1-homologue as racemic dl-alpha-tocopherol, which according to present nomenclature is designated as all-rac-alpha-tocopherol, and is a mixture of 8 stereoisomers.
Alpha-tocopherol is produced commercially for use as a feed supplement for domestic animals as a source of Vitamin E activity and as a nutrient supplement for humans. Tocopherols are also used in food technology as an anti-oxidant to retard the development of rancidity in fatty materials.
The tocopherols are found widely distributed in normal foods, occurring in the highest concentration in the cereal grain oils, principally in corn and wheat oils, but also in barley and rye. They are also found in vegetable oils such as safflower, soybean, peanut, cottonseed, linseed, sunflower, rapeseed and palm, and in other vegetable sources, e.g. palm leaves, lettuce, alfalfa, rubber latex and a variety of other plant materials. The proportion of the most active form, the d-alpha-tocopherol varies widely among the different sources. Two of the highest sources of dalpha-tocopherol is safflower oil and sunflower oil, though the most commonly available source is soybean oil, which has a considerably lower percent of d-alpha-tocopherol with significantly higher percentages of the gamma- and deltahomologues. In addition to being a source for tocopherol homologues, palm oil, oats, rye, and barley also contain tocotrienol.
The naturally occurring tocopherols are generally isolated from natural products such as vegetable oil sources by various combinations of such procedures as esterification, saponification, extraction, distillation, ion-exchange, adsorption chromatography, precipitation of sterols, crystallization, and many others. The tocopherol concentrate isolated in this manner will vary depending on the particular vegetable source and separation techniques used. Generally however, the concentrate is a mixture of tocopherol homologues containing about 40% or more impurities such as residual sterols, hydrocarbons, and fatty acids. This concentrate containing up to about 60% mixed tocopherol homologues is suitable for further processing to produce dalpha-tocopherol of 90% or greater purity. The non-alphatocopherols in the mixture can be converted to the more biologically active d-alpha-tocopherol by introducing methyl substituents into the aromatic ring (Tocol ring). A variety of ways are known for achieving this upgrading. The methylation can be done by halomethylation, aminomethylation, hydroxy-alkylation or formylation to introduce a methyl functional group followed by reduction to give the methylated tocopherol.
Various prior art alkylation methods are known, including aminoalkylation as described for example in Weisler U.S. Pat. Nos. 2,486,539 and 2,519,863. These methods are generally applied to low potency tocopherols extracted from plant sources by reacting the mixed tocopherols with an amino-alkylating agent, suitably piperidine hydrochloride and paraformaldehyde in an ethanol solvent acidified with hydrochloric acid. The amino alkyl addition product of mixed tocopherols is then reduced by catalytic hydrogenation to convert the non-alpha tocopherols in the mixture to alpha-tocopherol. Other alkylation methods, e.g. haloalkylation are also known. The haloalkylation reaction is preferably a chloromethylation achieved by reaction of the non-alpha-tocopherols present with a solution of formaldehyde in the presence of a hydrogen halide such as hydrogen chloride. This results in the introduction of a chloromethyl group. Other chloroalkyl groups may be introduced by using the corresponding aldehydes. This chloromethyl group is converted into a methyl group by a reduction procedure using stannous chloride and hydrochloric acid. Zinc and HCl reduction may also be employed instead of stannous chloride which is preferred. A simultaneous chloromethylation and reduction may be conducted in a single step by adding the stannous chloride to the initial reaction mixture thereby producing the methylation in a single stage process.
Other methods of alkylating tocopherols include the formylation methods described in U.S. Pat. No. 2,592,531 in which mixed tocopherols are reacted with formaldehyde in the presence of an organic acid catalyst. More recently, Japanese Patent No. 79-143,054 describes a process for preparing alpha-tocopherol from mixed tocopherols by reacting with formaldehyde and a reducing agent in the presence of an organic acid, to convert the non-alpha-tocopherols directly to alpha-tocopherol by hydroxymethylating and reducing in a single stage. Other acid catalysts such as phosphoric and boric acid can also be utilized as shown in U.S. Pat. Nos. 3,819,657 and 3,338,922.
All of these prior art methods generally involve converting the non-alpha-tocopherols in the mixture to alphatocopherols along with the alpha-tocopherol originally present in the mixture as high potency d-alpha-tocopherol. None of these methods involve separating the d-alpha-tocopherol from its beta-, gamma- and delta- homologues and thereafter upgrading only the mixture of non-alpha-tocopherol homologues to the high potency d-alpha-tocopherol form.
It has now been found, that by aminoalkylation of mixed tocopherols the amino adducts of the non-alpha-tocopherol homologues are provided, which can be readily separated from any alpha-tocopherol. The sterol and hydrocarbon impurities also present in the mixed tocopherol starting materials remain with the original alpha-tocopherol fraction. Alphatocopherol can be recovered in high purity by separating from the sterol and hydrocarbon impurities, without having to handle also the homologue tocopherols. Furthermore, the homologue materials which are obtained from the separation in high purity can be readily converted to the d-alpha- form in high yield and high purity. Moreover, it should be noted that this invention can be used to isolate the naturally produced d-alpha-tocopherol, and to upgrade the natural nonalpha-tocopherols present.
Accordingly, it is an object of this invention to provide a method for separating natural d-alpha-tocopherol from plant materials containing a mixture of tocopherol homologues. It is a further object of this invention to provide a method for separating d-alpha-tocopherol from a mixture of alpha-, and one or more of its beta-, gamma- and deltahomologues by reacting the mixture with a reagent which forms with the beta-, gamma- and delta- homologues derivatives that can be readily separated from the unreacted alpha-tocopherol present in the mixture. Yet another object of the invention is to prepare salts of the amine adducts of beta-, gamma- and delta-tocopherols which can be readily isolated from a mixture containing alpha-tocopherol.
Still another object is to provide new intermediates in the conversion of beta-, gamma- and delta-tocopherols to alpha-tocopherol. Still another object of the invention is to provide novel methods for methylating beta-, gamma- and delta-tocopherols. These and other objects can be more fully understood from the following description and working embodiments which are more fully set out below.